Open research questions in Cardiac electrophysiology and arrhythmias

What the literature leaves open

• Abstract Background and Aims Congenital long QT syndrome (LQTS) is a heterogeneous disorder in which genotype and QTc duration modulate the risk of major arrhythmic events (MAEs), but contemporary paediatric outcome data remain limited.

  Paediatric long QT syndrome: clinical outcomes and therapy in the Spanish National Registry · 2026 · DOI

• Accordingly, com- bined RR–QTc–RQA may serve as a stage-aware, noninvasive biomarker of cardiac health in pediatric oncology; validation in larger, exposure-stratified longitudinal cohorts is warranted.

  Recurrence-quantification analysis of heart-rate variability and QT-interval variability in pediatric cancer therapy · 2026 · DOI

• This study enhances the understanding of genetic contributions to cJET and suggests further investigation of POPDC2 in other forms of supraventricular tachyarrhythmias.

  Exome Sequencing Identifies POPDC2 as a Candidate Gene for Familial Congenital Junctional Ectopic Tachycardia · 2026 · DOI

• BackgroundWomen experience drug-induced Torsades de Pointes (TdP) at approximately twice the rate of men across more than 50 QT-prolonging drug classes, yet the quantitative ionic basis of this sex disparity remains incompletely characterised.

  Sex-specific amplification of IKr-blocker-induced action potential prolongation by reduced female IKs repolarization reserve: a computational study using the O'Hara-Rudy human ventricular model · 2026 · DOI

• Many drugs that block voltage-gated K+ channels encoded by the human Ether-a-go-go-Related Gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear.

  A hERG Blocker Facilitates K+ Channel Current by Agonizing Pore Opening while Blocking · 2026 · DOI

• Most ATS1 variants disrupt channel regulation by phosphatidylinositol 4,5-bisphosphate (PIP2), but whether specific mutations confer differential arrhythmic risk remains unclear.

  Risk Stratification of Arrhythmogenic Consequences of Andersen-Tawil Syndrome Affecting Kir2.1-PIP2 Interactions · 2026 · DOI

• The emergence of CRDS as a distinct clinical entity associated with RyR2 LOF mutations represents a significant advancement in our understanding of the complex genetics and pathophysiology of cardiac diseases. Unlike the classic RyR2 GOF disorders such as CPVT, CRDS is characterized by RyR2 LOF mutations that impair systolic Ca2+ release, leading to distinct electrophysiological remodeling including enhanced ICaL, altered NCX activity, and action potential prolongation, which predisposes patients to EADs and arrhythmias. The identification of CRDS underscores the importance of comprehensive genetic screening in patients presenting with arrhythmias or other cardiac dysfunction, particularly when traditional diagnostic approaches fail to yield a definitive diagnosis. Notably, CRDS patients often exhibit negative EST results, necessitating distinct diagnostic tools such as the LBLPS stimulation protocol.

  Calcium release deficiency syndrome: an emerging ryanodinopathy · 2026 · DOI

• et al., 2018) - would significantly enhance its predictive power. In this direction, the Disease Maps community (https://disease-maps.io/) has demonstrated that mechanistic, highly detailed molecular maps enable systematic integration of multi-omics data and contextual interpretation of dynamic processes, providing a promising blueprint for advancing AOPs beyond static representations and tools for benchmarking existing networks (Ladeira et al., 2025; Mazein et al., 2018; Staumont et al., 2025). Moving from the mostly high-level representation of biological activities in the AOP- Wiki towards more detailed molecular maps would improve interpretability of and mechanistic experimental outcomes grounding. This does not require enforcing excessive pathway granularity but can be achieved through complementary strategies such as ontology mapping, pathway enrichment analysis, and the application of computational approaches for quantitative AOP modelling (Jaylet et al., 2024; Knapen et al., 2018). A significant challenge encountered during this work was the lack of standardisation in the AOP-Wiki, a scenario also identified in other mapping studies (Jaylet et al., 2024). Many KEs describing the same biological process were titled differently, requiring manual harmonisation to build a coherent network. For instance, events with overlapping biological scope were recorded under multiple names and with different levels of detail, which fragments knowledge and complicates automated network generation. These redundancies have been explicitly noted for ROS-related KEs, where multiple nuanced entries exist despite referring to similar processes, prompting the launch of the “Mystery of ROS” initiative to create harmonised consensus KEs (Tanabe et al., 2022; Tanabe et al., 2023). Such efforts highlight the broader need for ontology-based alignment of KE terminology, ensuring consistency in descriptors like directionality, biological objects, and processes to make entries machine-readable and interoperable. This demand has been echoed by the Advancement of AOPs Knowledgebase Interest Group (SKIG), which has prioritised ontology-driven and development of umbrella KEs as central steps towards AOP-Wiki 3.0 (Wittwehr et al., 2025). In parallel, the recently launched SCAHT AOP_HUB provides a practical forum for training, knowledge exchange, and discussion of recurring challenges in AOP development, with a strong focus on engaging early-career researchers (Coerek et al., 2025). Together, these initiatives is actively addressing the demonstrate that the community standardisation bottleneck and moving towards a more interoperable and predictive AOP knowledge base.

  Cardiotoxicity adverse outcome pathway network: towards mechanistic and quantitative modelling · 2026 · DOI

• Even though the 3 studies were all designed specifically to study VF during first STEMI, comprised a large population, and comprehensively phenotyped individuals, our findings should be interpreted considering several limitations, some of which have already been mentioned earlier. Observational studies are always at risk of confounding, and even though we adjusted based on a thorough evaluation of causal pathways, we cannot rule out unmeasured confounding. Only patients who arrived at the hospital and received reperfusion therapy were included in the studies. Thus, some selection bias is pre- sent: patients with VF as their first symptom and/or unwit- nessed cardiac lower probability of resuscitation and survival until hospitalization. As a result, the phenotype of VF cases in this study is not necessarily the same as in all victims to SCD caused by CAD, and results cannot necessarily be extrapolated to populations not included in the study population. arrest have a Patients were interviewed after the event, which increases the risk of recall bias. Patients who have had a cardiac arrest may be more prone to recall SD in their family; however, we believe this risk to be small. After a cardiac arrest, patients may experience retrograde amnesia, or if still comatose, the relatives may be unaware of the immediate circumstances or history. This increases the prevalence of missing data not at random of patients in the case group. Patients using antiar- rhythmic drugs were excluded from the study so results cannot be extrapolated to this subgroup. For example, this might have selected patients with less symptomatic AF, and it is difficult to judge whether results would be the same in in- dividuals receiving, for example, class I or III antiarrhythmic drugs. Finally, the results are vulnerable to misclassification of cases. Postresuscitation ECGs and cardiac enzymes can be difficult to interpret, and deciding whether cardiac arrest judgment. is caused by acute MI demands strong clinical Falsely including cases with a different phenotype, for example, primary arrhythmia or chronic ischemia, could alter the results. Thorough evaluation and adjudication of cases have been done to minimize this effect. Finally, the study is epidemiologic in nature, and further studies are needed to assess genetic, electrical, and mechanistic insights into the ar- rhythmogenesis during acute ischemia.

  Risk factors associated with ventricular fibrillation during first ST-elevation myocardial infarction: Individual participant data analysis of 3 prospective case-control studies · 2026 · DOI

• This study analyses the Ta wave using spline-interpolated single beats rather than continuous real-time ECG re- cordings, which may limit the representation of beat-to-beat variability. Additionally, the modified limb lead (MLL) and atrioventricular block (AVB) reference ECGs used for indi- rect validation were not recorded simultaneously with the standard 12-lead ECGs; therefore, direct beat-to-beat equiv- alence cannot be definitively established. The analysis is also restricted to conditions where Ta waves are visually iden- tifiable, and therefore does not account for scenarios in which Ta waves remain fully masked by the QRS complex such as in SR. Hence, reliable Ta-wave extraction in SR may not always be feasible. Additionally, the sample size for atrial tachyarrhythmias is limited, and inter-lead variations in Ta wave expression were not extensively evaluated. investigations into disease-specific Ta wave alterations. Hence, this article presents that further studies on the Ta wave features may be advantageous in detecting and pre- dicting the atrial arrhythmias. Future research on Ta wave characteristics could play a crucial role in minimizing false positive diagnosis of MI. Acknowledgments: The authors acknowledge the support from the Ministry of Education, Government of India, to carry out this research. Research ethics: The recordings were acquired from vol- unteers in National Institute of Technology Rourkela by the institutional ethics committee (NITR/IEC/2023/M/04; dated 19/07/2023) and in accordance with the ethical guidelines of Helsinki Declaration. Atrial Tachycardia, AVB ECGs and myocardial ischemic TMT ECG was acquired from the Jai- prakash Hospital and Research Centre from the ethics committee (JPHRC/EC/A16; dated 12/01/2023). Informed consent: Informed consent was obtained from all individuals included in this study. Author contributions: All authors have accepted re- sponsibility for the entire content of this manuscript and approved its submission. Use of large language models, AI and machine learning tools: Chat GPT was referred to improve language for some texts of the manuscript. Conflict of interest: The authors state no conflict of interest. Research funding: This work was supported by financial grants from the Anusandhan National Research Foundation (ANRF), Government of India (CRG/2023/007815). Data availability: Data will be provided upon request.

  Atrial repolarization wave: a new approach using spline-based feature engineering and explainable AI for atrial arrhythmia diagnosis · 2026 · DOI

• The case emphasizes the importance of thoughtful consideration of device strategy in refractory VT management, but lacks systematic guidelines for when to employ overdrive pacing versus other therapeutic modalities.

  Treatment of Ventricular Tachycardia Storm with Transvenous Overdrive Pacing in a Patient with a Normal QT Interval · 2026 · DOI

• While pacing for PVC-induced VT may not be novel, this case contributes educational value by demonstrating its utility in a real-world scenario outside of long QT contexts, suggesting a need for further prospective studies beyond case reports.

  Treatment of Ventricular Tachycardia Storm with Transvenous Overdrive Pacing in a Patient with a Normal QT Interval · 2026 · DOI

• Radiofrequency ablation was not feasible overnight and was ultimately deferred during admission given multifocal PVC triggers without a clear dominant trigger, indicating a need for better patient selection criteria for ablation candidacy.

  Treatment of Ventricular Tachycardia Storm with Transvenous Overdrive Pacing in a Patient with a Normal QT Interval · 2026 · DOI

• These findings suggest that if a drug inhibits CYP2J2 and interacts with one of these four residues, then it may have a higher risk of QT prolongation and more preclinical studies are warranted to assess cardiovascular safety.

  Investigating the association between CYP2J2 inhibitors and QT prolongation: a literature review · 2024 · DOI

• Bazett formula has disadvantages on QT correction in patients with heart rates more than 100 bpm and lower than 60 bpm, potentially resulting in underestimated DQTc values.

  Evaluation of Corrected QT Intervals of 74 COVID19 Patients Treated with Hydroxychloroquine in Combination with or without Azithromycin and/or Favipiravir · 2022 · DOI

• Prediction and prevention of electrical myocardial instability in patients with hypertension without / and in combination with ischemic heart disease, based on a study of the relationship between the presence of frequent ventricular extrasystole, such as electrical myocardial instability, and plasma fibrosis biomarkers (aldosterone, galectin-3 and transforming growth factor-β1) have not been clarified in the studies.

  Electrical myocardial instability as a problem of modern therapeutic practice – the realities of prognosis (a literature review) · 2020 · DOI

• Nevertheless, except for case reports and experimental trials about QT/QTc, there are insufficient data in the literature on the incidence of cardiac arrhythmias detected by electrocardiography (ECG) and Holter monitoring.

  Evaluation of cardiac arrhythmia incidence in patients treated with oral moxifloxacin · 2019 · DOI

• Despite the use of advanced molecular biology techniques and recommendations suggesting autopsy studies of young people who died suddenly, still even half the SCD incidents in young people remains unclear.

  Idiopatyczne migotanie komór u 30-letniego mężczyzny – opis przypadku · 2017 · DOI

• Unfortunately, despite its simplicity and utility, ECG is insufficiently sensitive and specific to be the single tool in the recognition of RV pathologies.

  Zastosowanie elektrokardiografii w ostrych i przewlekłych chorobach z zajęciem prawej komory serca. · 2016 · DOI

• Anesthetic and sedative agents are widely used in electrophysiology laboratories, operating rooms, and intensive care units, yet their direct effects on cardiac conduction and arrhythmia risk are often underrecognized.

  Anesthetic-Electrophysiologic Interactions: How Sedatives Shape Cardiac Conduction and Arrhythmia Risk · 2026 · DOI

• As far as we are aware, one has not yet quantified the number and affinity of GLP-1 receptors in the human heart.

  Contractile effects of dulaglutide in the human atrium · 2026 · DOI

• Background: Congenital junctional ectopic tachycardia (cJET) is a rare, potentially life-threatening arrhythmia suspicious for a genetic basis, yet its molecular underpinnings remain incompletely defined.

  Exome Sequencing Identifies POPDC2 as a Candidate Gene for Familial Congenital Junctional Ectopic Tachycardia · 2026 · DOI

• The relationship between cerebral contusion and hemorrhage, and SCD is complex and not yet fully understood.

  Unveiling the cause of sudden cardiac death: a macroscopic and microscopic analysis at the Institute of Forensic Medicine, Cluj-Napoca (Romania) · 2025 · DOI

• The lower rates of severe QTc prolongation might be due to exclusion of severe patients in the study, limiting applicability to more critically ill populations.

  Evaluation of Corrected QT Intervals of 74 COVID19 Patients Treated with Hydroxychloroquine in Combination with or without Azithromycin and/or Favipiravir · 2022 · DOI

• Their use ismostly confined to critically ill patients whose hemodynamic impairment is such that tissue perfusion is insufficient to meet metabolic requirements (2).

  Inotropes and vasopressors · 2017 · DOI

Most-cited papers in Cardiac electrophysiology and arrhythmias

• Myocardial ischemia/reperfusion: Translational pathophysiology of ischemic heart disease · Med · 2024 · 190 citations
• Recent Advances in Antiarrhythmic Drug Therapy · Drugs · 2023 · 67 citations
• The Phenothiazine Drugs Inhibit hERG Potassium Channels · Drug and Chemical Toxicology · 2005 · 41 citations
• Empagliflozin significantly attenuates sotalol-induced QTc prolongation in rats · Kardiologia Polska · 2020 · 21 citations
• Muscarinic Receptors in Cardioprotection and Vascular Tone Regulation · Physiological Research · 2024 · 15 citations
• Sex Related Differences in Electrocardiography · Physiological Research · 2023 · 13 citations
• Structure-Function Relationships and Modifications of Cardiac Sarcoplasmic Reticulum Ca2+-Transport · Physiological Research · 2021 · 13 citations
• Cough as a Cause and Consequence of Heart Dysfunction - Current State of Art · Physiological Research · 2020 · 12 citations
• Effect of overweight on P-wave and QT dispersions in childhood · Turk Kardiyoloji Dernegi Arsivi-Archives of the Turkish Society of Cardiology · 2013 · 8 citations
• Remembering the canonical discoverers of the core components of the mammalian cardiac conduction system: Keith and Flack, Aschoff and Tawara, His, and Purkinje · AJP Advances in Physiology Education · 2022 · 8 citations

Most recent work

• Risk factors associated with ventricular fibrillation during first ST-elevation myocardial infarction: Individual participant data analysis of 3 prospective case-control studies · Heart Rhythm · 2026
• Ohmic and viscous damping of inner core translational oscillations · Earth and Planetary Science Letters · 2026
• Contribution of Non-Sustained Ventricular Tachycardia to the Primary Prevention of Sudden Cardiac Death ― Validation of Current Japanese Circulation Society / Japanese Heart Rhythm Society Guideline Recommendations in the Nippon Storm Study ― · Circulation Journal · 2026
• Treatment of Ventricular Tachycardia Storm with Transvenous Overdrive Pacing in a Patient with a Normal QT Interval · Case Reports and Case Series in Cardiology Journal · 2026
• Assessment of Heart Rate and Cardiac Repolarization Parameters in the Prone Position in Young Healthy Men · Medicine and Biotechnology · 2026
• Modeling the spatiotemporal properties of crosstalk between RyR-mediated and IP3R-mediated local Ca2+ release · Frontiers in Cell and Developmental Biology · 2026
• Polygenic risk modulates myocardial repolarization and T-wave geometry in congenital long-QT syndrome type 1: evidence from digital ECG phenotyping · Frontiers in Cardiovascular Medicine · 2026
• Anatomically Accurate, Humanized Arrhythmia Modeling: Toward Organ Engineering · Circulation Research · 2026
• Postmortem genetic testing in sudden death: clinical and medico-legal implications · International Journal of Legal Medicine · 2026
• Atrial repolarization wave: a new approach using spline-based feature engineering and explainable AI for atrial arrhythmia diagnosis · Biomedical Engineering / Biomedizinische Technik · 2026

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